A continuación, les presentamos datos y proyecto intacto de los investigadores
DR. SANCHEZ-DUFFHUES, GONZALO
University Education
1998-2005 BSc. Biochemistry. University of Cordoba (ESP).
2007-2009 MSc. Nutrition and Metabolism. University of Cordoba (ESP).
2005-2011 PhD in Biochemistry. Cum Laude. University of Cordoba (ESP).
Professional Experience (selection)
2007-2011 PhD student. University of Cordoba. ESP.
2011-2015 Postdoctoral research fellow. Leiden University Medical Center, NL.
2015-2020 Senior researcher. Leiden University Medical Center, NL.
2020- Assistant Professor. Leiden University Medical Center, NL.
Scientific Scope & Research Field
Dr. G. Sanchez-Duffhues (GSD) leads a team using rare TGF- monogenic human diseases (including FOP) as models to interrogate TGF- signaling and modulate cell plasticity with translational application in fibrosis, cardiovascular disease and calcifying disorders. During his career, GSD has accumulated an extensive publication record (“h” index 24, ORCID: 0000-0002-3205-0710), including first and last author manuscripts, and obtained his own funding (over €1M), including awards in competitive grant programs, biotech service fees, and personal awards. He is an internationally recognized expert in TGF- signaling, as evidenced by his elected membership to the European Calcified Tissue Society Young Academy, and 1st Marshall Urist young BMP investigator award. GSD has followed supervision and management training to effectively guide his team (currently including 4 PhD students, 1 technician, 3 undergraduate students), often in collaboration with a growing network of some of the best groups in the field. He is committed to dissemination activities within the FOP community and a regular speaker in international FOP patient gatherings.
Most Relevant Publications (last 5 years)
- Gomez-Puerto MC, Iyengar PV, Garcia de Vinuesa A, Ten Dijke P, SanchezDuffhues G. Bone morphogenetic protein receptor signal transduction in human disease. J Pathol. 2019;247(1):9-20.
- Sanchez-Duffhues G et al. Endothelium-derived stromal cells contribute to hematopoietic bone marrow niche formation. Cell Stem Cell. 2021;28(4):65370 e11.
- Fortin J, Tian R, Zarrabi I, Hill G, Williams E, Sanchez-Duffhues G, et al. Mutant ACVR1 Arrests Glial Cell Differentiation to Drive Tumorigenesis in Pediatric Gliomas. Cancer Cell. 2020;37(3):308-23 e12.
- Szulcek R, Sanchez-Duffhues G, Rol N, Pan X, Tsonaka R, Dickhoff C, et al. Exacerbated inflammatory signaling underlies aberrant response to BMP9 in pulmonary arterial hypertension lung endothelial cells. Angiogenesis. 2020;23(4):699-714.
Sanchez-Duffhues G. et al. Cripto favors chondrocyte hypertrophy via TGFbeta SMAD1/5 signaling during development of osteoarthritis. J Pathol. 2021;255(3):330-42.
Host Institution
Leiden University Medical Center (LUMC). Department of Cell and Chemical Biology.
Address: Albinusdreef 2. 2333 ZA, Leiden, The Netherlands. Phone: +31715269264
Website:
https://ccb.lumc.nl/research/cardiovascular-cell- biology149/gonzalo-sanchez-duffhues-220
DR. VENTURA PUJOL, FRANCESC
University Education
1987 BSc. Chemistry. University of Barcelona (ESP).
1992 PhD in Biochemistry. Cum Laude. University of Barcelona (ESP).
Professional Experience (selection)
1989-1992 PhD student. University of Barcelona, ESP.
1992-1995 Postdoctoral research fellow. Sloan-Kettering Cancer Institute, US.
1995-2011 Assistant Professor. University of Barcelona, ESP.
2011- Full Professor. University of Barcelona, ESP.
Scientific Scope & Research Field
The research group led by Dr. Francesc Ventura has been conducting active research for the last 28 years on the mechanisms of signal transduction and transcriptional activation during bone development and bone homeostasis. This experience in molecular and cellular bone biology has been the origin of translational objectives and approaches to new treatments for bone pathologies. The group (currently including 1 postdoctoral, 2 PhD students and 1 technician), is currently studying various aspects of functional genomics in bone biology. Bone pathophysiology, bone regeneration and osteointegration:
- Stem cells as a therapeutic strategy for bone regeneration.
- Pathophysiology and therapeutic alternatives for the treatment of FOP.
- Preclinical analysis of C5aR inhibitors as new therapies for osteoporosis.
During his career, Dr. Ventura has accumulated over 140 publications (“h” index 40), received numerous awards (ICREA young investigator, Fulbright) and currently has a number of competitive research grants (MICINN, Marató TV3, IFOPA, FOPItalia, etc.)
Most Relevant Publications (last 5 years)
- Sanchez-de-Diego C, Pedrazza L, Pimenta-Lopes C…Ventura F. NRF2 function in osteocytes is required for bone homeostasis and drives osteocytic gene expression. Redox Biol. 2021;40:101845.
- Valer JA, Sanchez-de-Diego C, Gamez B, Mishina Y, Rosa JL, Ventura F. Inhibition of phosphatidylinositol 3-kinase alpha (PI3Kalpha) prevents heterotopic ossification. EMBO Mol Med. 2019;11(9):e10567.
- Sanchez-de-Diego C, Artigas N, Pimenta-Lopes C… Ventura F. Glucose Restriction Promotes Osteocyte Specification by Activating a PGC- 1alphaDependent Transcriptional Program. iScience. 2019;15:79-94.
- Artigas N, Gamez B, Cubillos-Rojas M… Ventura F. p53 inhibits SP7/Osterix activity in the transcriptional program of osteoblast differentiation. Cell Death Differ. 2017;24(12):2022-31.
- Ventura F, Williams E, Ikeya M, Bullock AN, Ten Dijke P, Goumans MJ, et al. Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva. Biomedicines. 2021;9(2).
Host Institution
Fundacio Institut D’Investigacio Biomedica de Bellvitge. Address: 08907. Hospitalet de Llobregat, Spain.
Phone: +34934024281
Website:
https://idibell.cat/en/research/translational- medicinearea/diabetes-and-metabolism-program/cell-signalling-and-bone-biology/
PI3K inhibitors as a new therapy for Fibrodysplasia ossificans progressiva (FOP)
Principal investigators:
Dr. Francesc Ventura Pujol (University of Barcelona, Barcelona, Spain): UNIB.
Dr. Gonzalo Sanchez-Duffhues (Leiden University Medical Center, Leiden, The Netherlands): LUMC
LAY SUMMARY
Heterotopic ossification (appearance of bone at non-appropriate sites) is a pathological process induced by trauma, such as hip arthroplasty (occurs in up to 40% of the cases), severe burns (up to 20% of highdegree burns), bone fractures and dislocations, or spinal cord injury. Heterotopic ossification is also a consequence of mutations in the ACVR1 gene in patients of the extremely rare disease Fibrodysplasia ossificans progressiva (FOP). In both cases, these events affect skeletal muscle, tendons and ligaments and result in episodic formation of extra-skeletal bone. Ectopic bone formation in FOP patients is progressive and cumulative, promotes immobilization of joints and forms a second skeleton that imprisons the body causing a premature death. Furthermore, patients with FOP are at constant risk of suffering cardiorespiratory conditions. Currently there is no proven effective treatment for this extremely disabling rare genetic disease. The actual management is only supportive, using anti-inflammatory drugs in acute pathological flare-ups of bone formation, with limited efficacy. Recently, we have discovered that BYL 719, a drug recently approved by drug agencies for other pathologies, could become a useful therapy for patients suffering from FOP. Therefore, using BYL719 for treatment of FOP, at least during a restricted temporal window, should pose few contraindications. We found that, in mice carrying the same gene mutation than FOP patients, BYL719 blocked the formation of bone without any adverse effect. However, in order to set the base for a clinical treatment, further studies are required to optimize dosing and timing of administration of BYL719 in both episodic and spontaneous ossification in FOP patients. In addition, whereas the mechanisms by which BYL719 works for the treatment of some types of tumors are characterized, to date it is not clear why this drug works in FOP. Therefore, we must know much better how BYL719 works in the treatment of FOP. For instance, understand its mechanism of action and to which osteogenic cells its action is required. This information becomes key to set the basis of future clinical trials and develop an efficient and safe treatment for FOP.
BUDGET
This project currently has support from FOP Italia (€100K) and TV3-La Marató (€289K). Additional budget (in euros) requested (for 1 year):
CONCEPT | LUMC (NL) | UNIB (ES) | TOTAL |
Personnel | 15.791,00 | 10.000,00 | 25.791,00 |
Equipment | 0,00 | 0,00 | 0,00 |
Consumables Travel | 5.209,00 0,00 | 10.000,00 0,00 | 15.209,00 0,00 |
Animal testing | 0,00 | 0,00 | 0,00 |
Outsourcing | 4.000,00 | 5.000,00 | 9.000,00 |
Shipping | 0,00 | 0,00 | 0,00 |
Publications | 0,00 | 0,00 | 0,00 |
Patents | 0,00 | 0,00 | 0,00 |
Other expenses | 0,00 | ||
SUBTOTAL | 0,00 | 0,00 | 0,00 |
Overhead 25% | 0,00 | 0,00 | 0,00 |
TOTAL | 25.000,00 | 25.000,00 | 50.000,00 |
Fibrodysplasia ossificans progressiva: de-Activatin’ ectopic Bone Lesions
Principal investigators:
Dr. Francesc Ventura Pujol (University of Barcelona, Barcelona, Spain): UNIB.
Dr. Gonzalo Sanchez-Duffhues (Leiden University Medical Center, Leiden, The Netherlands): LUMC
LAY SUMMARY
Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by bone formation at ectopic sites (heterotopic ossification, HO), triggered by minor tissue trauma. Surgical removal of heterotopic bone, intramuscular injections (i.e., vaccination), viral infections, etc provoke painful episodes of rapid new bone formation named flare-ups. Unfortunately, there is no cure for FOP yet. FOP is caused by mutations in the ACVR1 gene, encoding the protein ALK2. The mutant ALK2 turns muscle cells into bone cells in response to a growth factor named Activin A, which is released in the muscle upon tissue damage.
Pharmacological blockade of Activin prevents HO, thereby highlighting the relevance of Activin in FOP progression. Our aim is to develop novel technologies to monitor Activin levels in FOP. This will lead to new tools to predict flareups and facilitate the treatment of patients with FOP. To achieve this overarching goal, we will apply stateof-art technologies in FOP disease mouse models, develop humanized FOP bone-on-chip devices with patient-derived cells resembling FOP lesions and identify molecules with biomarker potential to improve the life quality of FOP patients.
BUDGET
This project has been proposed for funding to the current call of the European Joint Programme on Rare diseases from the EU Commission. Additional budget (in euros) requested (for 1 year):
CONCEPT | LUMC (NL) | UNIB (ES) | TOTAL |
Personnel | 10.527,00 | 5.000,00 | 15.527,00 |
Equipment | 0,00 4.473,00 | 0,00 10.000,00 | 0,00 |
Consumables Travel | 14.473,00 0,00 | ||
0,00 | 0,00 | ||
Animal testing | 0,00 | 0,00 | 0,00 |
Outsourcing | 10.000,00 | 10.000,00 | 20.000,00 |
Shipping | 0,00 | 0,00 | 0,00 |
Publications | 0,00 | 0,00 | 0,00 |
Patents | 0,00 | 0,00 | 0,00 |
Other expenses | 0,00 | ||
SUBTOTAL | 0,00 | 0,00 | 0,00 |
Overhead 25% | 0,00 | 0,00 | 0,00 |
TOTAL | 25.000,00 | 25.000,00 | 50.000,00 |
Organ-on-chips to resemble and interrogate ALK2 signalling in Fibrodysplasia ossificans progressiva
Principal investigators:
Dr. Francesc Ventura Pujol (University of Barcelona, Barcelona, Spain): UNIB.
Dr. Gonzalo Sanchez-Duffhues (Leiden University Medical Center, Leiden, The Netherlands): LUMC
LAY SUMMARY
Fibrodysplasia ossificans progressiva (FOP, MIM# 135100) is an ultra-rare congenital disorder where children experience episodic and painful tissue swellings in response to inflammatory insults (i.e., minor tissue trauma, vaccinations, surgical intervention), leading to extra-skeletal bone formation (heterotopic ossification, HO). Most patients become wheelchair-bound by their 30s. Furthermore, cardiovascular complications in FOP have been described, leaving patients at a constant risk of death due to thoracic insufficiency syndrome (median survival age is 40 years). As yet, there is neither any cure nor validated biomarkers available. A few putative treatment strategies are currently investigated in clinical trials, but the most clinically advanced have been recently interrupted due to adverse events. Therefore, there is an urgent need to identify safe and effective molecules to improve treatment and monitoring of FOP patients. All FOP patients carry a heterozygous gene point mutation in ACVR1, encoding the Bone morphogenetic protein (BMP) type I receptor ALK2. Through mechanisms poorly understood yet, the mutant ALK2 R206H receptor gains the ability to respond to Activin. While the Activin-ALK2 R206H axis has become an obvious therapeutic target for FOP, both ALK2 and Activins play key roles in cardiovascular homeostasis. This raises the possibility that systemic therapeutic targeting of ALK2 and Activins may trigger untenable side effects in FOP patients, eventually leading to drug development failure in late clinical studies. To investigate whether Activin and ALK2 mutant signalling compromises the cardiovascular health of FOP individuals, we will develop complex organ-onchip devices to mimic key vascular and cardiac environments with patient derived cells. These in advanced vitro models will help us to discard potential detrimental cardiovascular effects of promising therapies, thereby facilitating clinical translation into patients.
BUDGET
This project currently has partial support from The Dutch Heart foundation and the LUMC. Additional budget (in euros) requested (for 1 year):
Additional budget requested to initiate preliminary studies:
.
CONCEPT | LUMC (NL) | UNIB (ES) | TOTAL |
Personnel | 15.791,00 | 5.000,00 | 20.791,00 |
Equipment | 0,00 | 0,00 | 0,00 |
Consumables Travel | 9.209,00 0,00 | 20.000,00 0,00 | 29.209,00 0,00 |
Animal testing | 0,00 | 0,00 | 0,00 |
Outsourcing | 0,00 | ,00 | 0,00 |
Shipping | 0,00 | 0,00 | 0,00 |
Publications | 0,00 | 0,00 | 0,00 |
Patents | 0,00 | 0,00 | 0,00 |
Other expenses | 0,00 | ||
SUBTOTAL | 0,00 | 0,00 | 0,00 |
Overhead 25% | 0,00 | 0,00 | 0,00 |
TOTAL | 25.000,00 | 25.000,00 | 50.000,00 |
(TRADUCCIÓN PROYECTO)
Investigadores y objetivo
Una ventana temporal, debe presentar pocas contraindicaciones. Encontramos que, en ratones portadores del mismo gen mutación que los pacientes con FOP, BYL719 bloqueó la formación de hueso sin ningún efecto adverso. Sin embargo, Para establecer la base de un tratamiento clínico, se requieren más estudios para optimizar la dosificación y el momento. de la administración de BYL719 en osificación tanto episódica como espontánea en pacientes con FOP. Además, Considerando que los mecanismos por los que actúa BYL719 para el tratamiento de algunos tipos de tumores son caracterizado, hasta la fecha no está claro por qué este medicamento funciona en FOP. Por lo tanto, debemos saber mucho mejor cómo BYL719 funciona en el tratamiento de FOP. Por ejemplo, comprender su mecanismo de acción y a qué células osteogénicas se requiere su acción. Esta información se convierte en clave para sentar las bases de futuros ensayos clínicos y desarrollar un tratamiento eficaz y seguro para la FOP
PRESUPUESTO Este proyecto cuenta actualmente con el apoyo de FOP Italia (100K€) y TV3-La Marató (289K€). Presupuesto adicional (en euros) solicitado (durante 1 año): CONCEPTO LUMC (NL) UNIB (ES) TOTAL Personal 15.791,00 10.000,00 25.791,00 Equipo 0,00 0,00 0,00 Consumibles 5.209,00
10.000,00 15.209,00 Viajes 0,00 0,00 0,00 Experimentación con animales 0,00
0,00 0,00 Tercerización 4.000,00 5.000,00 9.000,00 Envío 0,00 0,00 0,00
Publicaciones 0,00 0,00 0,00 Patentes 0,00 0,00 0,00 Otros gastos 0,00
SUBTOTAL 0,00 0,00 0,00 Gastos generales 25% 0,00 0,00 0,00 TOTAL
25.000,00 25.000,00 50.000,00
Fibrodisplasia osificante progresiva: desactivación de lesiones óseas ectópicas Investigadores principales: Dr. Francesc Ventura Pujol (Universidad de Barcelona, Barcelona, España): UNIB. Dr. Gonzalo Sánchez-Duffhues (Centro Médico de la Universidad de Leiden, Leiden, Países Bajos): LUMC RESUMEN LAICOS La fibrodisplasia osificante progresiva (FOP) es una enfermedad rara caracterizada por la formación de hueso en el momento ectópico. (osificación heterotópica, HO), desencadenada por un trauma tisular menor. Extirpación quirúrgica de hueso heterotópico, inyecciones intramusculares (es decir, vacunas), infecciones virales, etc. provocan episodios dolorosos de hueso nuevo rápido formación denominada llamaradas. Desafortunadamente, todavía no existe una cura para la FOP. La FOP es causada por mutaciones en el Gen ACVR1, que codifica la proteína ALK2. El mutante ALK2 convierte las células musculares en células óseas en respuesta a un factor de crecimiento llamado Activin A, que se libera en el músculo cuando se daña el tejido. Farmacológico el bloqueo de Activin previene HO, destacando así la relevancia de Activin en la progresión de FOP. Nuestra puntería es desarrollar nuevas tecnologías para monitorear los niveles de Activin en FOP. Esto conducirá a nuevas herramientas para predecir brotes y facilitar el tratamiento de pacientes con FOP. Para lograr este objetivo general, aplicaremos tecnologías de última generación en modelos de ratón con FOP, desarrollaremos dispositivos humanizados de hueso en chip con FOP con células derivadas de pacientes que se asemejan a lesiones de FOP e identifican moléculas con potencial biomarcador para mejorar la calidad de vida de los pacientes con FOP.
PRESUPUESTO Este proyecto ha sido propuesto para su financiación a la convocatoria actual del Programa Conjunto Europeo sobre Raras enfermedades de la Comisión de la UE. Presupuesto adicional (en euros) solicitado (para 1 año):
aún poco conocidos, el mutante ALK2 R206H receptor adquiere la capacidad de responder a Activin. Mien14
tras que el eje Activin-ALK2 R206H se ha convertido en un obvio blanco terapéutico para FOP, tanto ALK2 como Activins juegan un papel clave en la homeostasis cardiovascular. Este plantea la posibilidad de que la orientación terapéutica sistémica de ALK2 y Activins pueda desencadenar efectos secundarios insostenibles efectos en los pacientes con FOP, lo que eventualmente conduce al fracaso en el desarrollo de fármacos en los últimos estudios clínicos. Investigar si la señalización mutante de Activin y ALK2 compromete la salud cardiovascular de las personas con FOP, desarrollará dispositivos complejos de órgano en chip para imitar entornos vasculares y cardíacos clave con el paciente células derivadas. Estos modelos in vitro avanzados nos ayudarán a descartar potenciales daños cardiovasculares efectos de terapias prometedoras, facilitando así la traducción clínica a los pacientes. PRESUPUESTO Este proyecto actualmente cuenta con el apoyo parcial de la fundación The Dutch Heart y LUMC. Presupuesto
adicional (en euros) solicitado (por 1 año)Presupuesto adicional solicitado para
iniciar estudios preliminares: CONCEPTO LUMC (NL) UNIB (ES) TOTAL Personal 15.791,00 5.000,00 20.791,00 Equipo 0,00 0,00 0,00 Consumibles
9.209,00 20.000,00 29.209,00 Viajes 0,00 0,00 0,00 Experimentación con
animales 0,00 0,00 0,00 Tercerización 0,00 ,00 0,00 Envío 0,00 0,00 0,00
Publicaciones 0,00 0,00 0,00 Patentes 0,00 0,00 0,00 Otros gastos 0,00
SUBTOTAL 0,00 0,00 0,00 Gastos generales 25% 0,00 0,00 0,00 TOTAL
25.000,00 25.000,00 50.000,00
Entrevistas relacionadas con la FOP.
https://www.facebook.com/96876562265/posts/pfbid02WBFSjbEjyKQRMTTy987ze4EXts9K8rTyvtoQv3HSGZ6nMuiZihx7vEhz85HQKMkl/
https://www.lavozdelsur.es/la-voz-seleccion/reportajes/valentina- contratiempo-es-enfermedad-rara-nina-jerez-amenaza-con- dejarlarigida_283903_102.html
https://www.lavozdelsur.es/ediciones/jerez/dura-batalla-padres-jerez-su- hijano-se-quede-como-estatua-esto-es-muy-cruel_268251_102.html
https://www.diariodejerez.es/jerez/Valentina-esperanzafibrodisplasia_0_1630039284.html?utm_source=facebook.com&utm_m edium=s mm&utm_campaign=noticias
Asociación de Apoyo a la investigación de la Fibrodisplasia Osificante Progresiva (FOP)
